Alkylation of DNA by C-10 of 2,7-diaminomitosene.
Mitomycin C and certain analogues alkylate DNA with their C-1 position and cross-link it by a second alkylation involving C-10. We now show that monoalkylation by C-10 (carbamate group) can occur for mitosene analogues that have no reactive C-1 functionality. Sodium dithionite reduction of 2,7-diaminomitosene or 2,7-diamino-1-hydroxymitosene in the presence of calf thymus DNA resulted in alkylation of the DNA to the extent of one molecule per 14 and 11 bases, respectively, although no covalent binding was observed on catalytic reduction. Reduction of each of these mitosenes by sodium dithionite in the presence of 2'-deoxyguanosine gave monoalkylation on the 2-amino group of this nucleotide. The 2,7-diaminomitosenes inhibited L-1210 leukemia cell colony formation in vitro at concentrations 3-4-fold greater (less potent) than mitomycin C. DNA single-strand breaks were also produced by each mitosene, but these lesions did not correlate with cytotoxicity and were less prominent than breaks produced by another monofunctional alkylating agent, methyl methanesulfonate. Mitosene-induced DNA strand breaks are probably due to excission-repair endonuclease activity and not from oxygen free radicals produced by redox cycling of the quinone moiety. There was no evidence of DNA-DNA cross-links by either 2,7-diaminomitosene.
Iyengar
B S
BS
Department of Pharmaceutical Sciences, University of Arizona, Tucson 85721.
Dorr
R T
RT
Shipp
N G
NG
Remers
W A
WA
D000478:Alkylation; D000818:Animals; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D004249:DNA Damage; D003849:Deoxyguanosine; D007939:Leukemia L1210 / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D008937:Mitomycins / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D015394:Molecular Structure; D013053:Spectrophotometry; D013056:Spectrophotometry, Ultraviolet
D008937:Mitomycins; C056707:2,7-diaminomitosene; D004247:DNA; D003849:Deoxyguanosine